Baclofen is a muscle relaxant and anti-spastic. Baclofen is useful for the alleviation of signs and symptoms of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. Baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In studies with animals, baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression. Baclofen is rapidly and extensively absorbed and eliminated. Absorption may be dose dependent, being reduced with increasing doses. Baclofen is excreted primarily by the kidney in unchanged form and there is relatively large intersubject variation in absorption and/or elimination.
The precise mechanism of action of baclofen as a muscle relaxant and anti-spasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter GABA, and may exert its effects by stimulation of the GABAB receptor subtype. Bowery N G, et al., Nature, 1980; 283:92-94; Bowery N G, et al., Neuroscience, 1987; 20:365-383; Bowery, N G, et al., Pharmacology Reviews, 2002; 54:247-264; Meythaler J M. Use of intrathecally delivered medications for spasticity and dystonia in acquired brain injury. Yaksh, editor. Spinal Drug Delivery. Elsevier, N.Y. 1999, pp. 513-554; LIORESAL® INTRATHECAL (baclofen injection) product insert.
Baclofen is a white to off-white, odorless or practically odorless crystalline powder, with a molecular weight of 213.66 g/mol. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform. LIORESAL® INTRATHECAL (baclofen injection) product insert.
Baclofen is currently the most effective treatment for severe spasticity and spastic hypertonia. This debilitating complication illustratively results from spinal cord injuries, multiple sclerosis, stroke, traumatic brain injuries, cerebral palsy and neurodegenerative diseases. Avellino A M, et al., Neuromodulation, 2000; 3:75-81. Spasticity is a debilitating complication that commonly leads to functional impairment, pain, and decreased personal independence. Id.
Oral baclofen therapy is approved. However, the oral therapy is commonly insufficient to reduce spasticity, and many patients are unresponsive. The high circulating concentrations of oral baclofen required for clinical efficacy produce numerous side effects including drowsiness, dizziness, weakness, ataxia, and confusion.
Administration of baclofen to patients with spinal or distal spasmodic conditions has proven to be a therapeutic challenge. Oral administration of baclofen is limited in that the maximum concentration of neural fluid baclofen is commonly insufficient to alleviate the spastic result of underlying etiology. Commonly, patients are unresponsive to oral baclofen administration or suffer intolerable side effects such as drowsiness, dizziness, weakness, ataxia, and confusion when efficacious levels of baclofen are present. Avellino, A M and Loeser, J D, Neuromodulation, 2000; 3:75-81.
In response to the non-optimal response to oral baclofen, programmable pump systems were developed that are implantable and provide a continuous infusion of baclofen directly to the cerebrospinal fluid. This method of delivery produces a more potent anti-spastic effect with fewer and less severe side effects. The pump is implanted subcutaneously whereby baclofen is transferred though a catheter to the lumbar region where it is passed through a Tuhoy needle directly into the cerebrospinal fluid. Albrigt, A L, et al., Neurosurgery, 2005; 56:93-97.
Intrathecal delivery of baclofen is more efficacious than oral delivery. However, it is not without complications. The most common complications include pump failure, infection, or migration of the catheter. Stempien, L, and Tsai, T, Am J Phys Med Rehabil, 2000; 79:536-41. However, cerebrospinal fluid (CSF) leaks are common with intrathecal delivery, particularly in children with cerebral palsy where an incidence rate of 6-15% is observed. Similar complications are also observed in adults at a rate of about 1%. Albrigt, A L, et al., Neurosurgery, 2005; 56:93-97. A possible explanation for CSF leakage is increased fluid pressure from the additional infusion volume from the pump or from occult hydrocephalus.
Baclofen is delivered intrathecally in saline that is loaded into the infusion pump by injection into a reservoir. The presence of the saline itself leads to toxicity and other complications. Injection of baclofen/saline solutions suffer neurotoxic complications resulting from their differing pH, osmotic pressure, membrane-active ion concentration, and CO2. Oka, K, et al., Neurosurgery, 1996; 38:733-736; Griffith H B, Endoneurosurgery: Endoscopic intracranial surgery, in Symon L (ed): Advances and Technical Standards in Neurosurgery. Wien, Springer-Verlag, 1986; 4:2-24; Griffith, H B, and Jamjoom A B, Br J Neurosurg, 1990; 4:95-100.
The use of directed intrathecal or intraventricular administration of baclofen either by bolus injection or by continuous or non-continuous infusion regulated by refillable, implantable pump systems has drastically improved the clinical feasibility of baclofen administration. However, baclofen has poor solubility in aqueous solutions necessitating high volumes of infused baclofen solution to achieve efficacious doses. Further, the 2 mg/mL maximum saline concentration has been inadequate to control the spasticity, hypertonia and symptoms of some patients. An additional difficulty is that mixing a 2 mg/mL baclofen injection with other drugs such as morphine or hydromorphone in “cocktails” to aid in control of pain can dilute the baclofen content to unacceptably low levels.
Baclofen is supplied as a solid powder form or tablet. Most commonly baclofen is provided in a solution of baclofen, sodium chloride, and water. These solutions generally do not require preservatives or other stabilizers as dissolved baclofen has been calculated to degrade less than 10% over a 10-year period when maintained at near neutral pH and room temperature. Ahuja, Analytical Profiles of Drug Substances, 1985; Vol. 14, New York: Academic Press, pp. 527-548.
The practical solubility of baclofen in aqueous solutions has been extensively investigated. The upper limit of aqueous solubility has been estimated to be 4.3 mg/ml. (Ahuja, 1985.) This was only achieved following long term dissolution of powder baclofen requiring weeks or months and merely represents an equilibrium suspension not suitable for intrathecal delivery. Increased solubility has been achieved in aqueous saline solution to as high as 12 mg/ml following extreme heating to as much as 100° C. and intense agitation such as by sonication, or high speed stirring. U.S. Patent Application Publication 2006/0009523. The drawbacks of this method are that creating baclofen solutions is time consuming and requires instrumentation not commonly found in a clinical setting. Another method that has shown some success is by initial dissolution in acid solution with pH levels below 3.87. Just prior to administration a base is added to bring the pH to pharmaceutically acceptable levels. This back titration method produces baclofen concentrations of nearly 10 mg/ml. U.S. Patent Application Publication 2006/0009523. However, strong acids or bases are required for the initial baclofen solvation that persist as a component of the clinically delivered baclofen solution. Unfortunately, saline solutions suffer neurotoxic complications resulting from their differing pH, osmotic pressure, membrane-active ion concentration, and CO2 making them unsuitable for intrathecal delivery directly into the CSF. Oka, K, et al., Neurosurgery, 1996; 38:733-736; Griffith H B: Endoneurosurgery: Endoscopic intracranial surgery, in Symon L (ed): Advances and Technical Standards in Neurosurgery. Wien, Springer-Verlag, 1986; 4:2-24; Griffith, H B, and Jamjoom A B, Br J Neurosurg, 1990; 4:95-100.
An alternative to saline or other aqueous solution for baclofen administration is artificial cerebrospinal fluid (aCSF). Differing forms of aCSF were previously used for in vivo pharmacological studies of baclofen administration. Jackson, G L, et al., Endocrinology, 2000; 141: 3940-3945; Goda, R. et al., J Chromatogr B Analyt Technol Biomed Life Sci, 2004; 801:257-64. However, the baclofen concentrations achieved in these and other studies were less than 0.21 mg/ml.
Thus, there exists a need for an improved solution in both concentration, stability, and compatibility with the CSF of baclofen for intrathecal delivery for the treatment of spasticity.